The complete reduction of oxygen by the univalent pathway results in the formation of superoxide anion radical, hydrogen peroxide, and hydroxyl radical (OH) as intermediates. These intermediates are too reactive to be tolerated in living tissue, and a variety of enzymatic mechanisms, which can bypass the electron spin restriction of oxygen and accomplish the divalent and tetravalent reduction of oxygen to water have evolved. Thus, most of the oxygen consumed by respiring cells is utilized by cytochrome oxidase, which reduces oxygen to water without releasing either superoxide or hydrogen peroxide. Despite this, in respiring cells at least some reduction of oxygen occurs via the univalent pathway.
The presence of superoxide radicals, hydrogen peroxide, and hydroxyl radicals has been demonstrated in phagocytic cells including neutrophils and monocytes. It has been shown that the oxygen free radicals not only cause direct damage to membranes and DNA, but also exert indirect effects such as de-regulation of cell proliferation and apoptosis, stimulation of angiogenesis, and modification of gene/protein expression. The cellular enzymatic defense mechanism against superoxide and hydrogen peroxide includes superoxide dismutase (SOD), catalase, and glutathione peroxidase.
At present, the pathologies and diseases which may be attributable to oxygen free radicals are numerous and include neuronal diseases such as brain infarction, brain edema, Parkinson's disease, and Alzheimer's disease; multiple sclerosis; lung diseases such as lung oxygen intoxication, chronic bronchitis, and adult respiratory distress syndrome; circulatory system diseases such as ischemic heart diseases (e.g., myocardial infarction and arrhythmia), and arteriosclerosis; and digestive organ diseases such as peptic ulcer, ulcerative colitis, and Crohn's disease.
Attempts have been made to apply scavengers of oxygen free radicals to treat the above-mentioned diseases. For example, recombinant SOD has become available and has been administered to patients. Acute myocardial infarction is one of its target diseases.
The specific interactions of cells with the extracellular matrix also play a critical role in the normal function of organisms. Alterations of the extracellular matrix are carried out by a family of zinc-dependent endopeptidases called matrix metalloproteinases (MMPs). The alterations are carried out in various cellular processes such as organ development, ovulation, fetus implantation in the uterus, embryogenesis, wound healing, and angiogenesis.
MMPs consist of five major groups of enzymes: gelatinases, collagenases, stromelysins, membrane-type MMPs, and matrilysins. The activity of MMPs in normal tissue functions is strictly regulated by a series of complicated zymogen activation processes and inhibition by protein tissue inhibitors for matrix metalloproteinases (“TIMPs”). Over-expression and activation of MMPs or an imbalance between MMPs and TIMPs have been suggested as factors in the pathogenesis of diseases characterized by the breakdown of extracellular matrix or connective tissues, including diseases such as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation which leads to restenosis and ischemic heart failure, and tumor metastasis (see, for example, Massova, I. et al. FASEB J. 1998, 12, 1075-1095). It has been suggested that these and other diseases may be treated by inhibiting metalloproteinase enzymes, thereby curtailing and/or eliminating the breakdown of connective tissues that results in the disease states.
The catalytic zinc in matrix metalloproteinases has been the focal point for inhibitor design. The modification of substrates by introducing zinc-chelating groups has generated potent inhibitors such as peptide and non-peptide hydroxamates and thiol-containing peptides. Peptide hydroxamates and the natural endogenous inhibitors of MMPs (TIMPs) have been used successfully to treat animal models of cancer and inflammation (see, for example, U.S. Pat. Nos. 5,300,501; 5,530,128; 5,455,258; and 5,552,419).
U.S. Pat. No. 6,468,537 and U.S. Patent Application Publication No. 2003/0021797 disclose peptides derived from nucleosomal histone proteins H1, H2A, H2B, H3, and H4, which are useful for delaying the onset and progression of systemic lupus erythematosus (SLE). U.S. Pat. No. 6,468,537 claims methods of treating an animal having systemic lupus erythematosus (SLE) and SLE-associated manifestations comprising administering to the animal one of the disclosed peptides, wherein the peptide is capable of promoting immunological tolerance, thereby treating SLE and the SLE-associated manifestations. While U.S. Pat. No. 6,468,537 discloses various peptides derived from different histones, among them a 15-mer peptide derived from H2A (amino acid residues 34 to 48), the peptides are disclosed solely as useful for promoting immunological tolerance in an animal having systemic lupus erythematosus.
International Patent Application Publication No. WO 03/017920 assigned to the applicant of the present invention discloses peptides for protection against inflammatory processes. The peptides were first isolated from the skin of a guinea pig exposed to a chemical or thermal burn and further exposed to iodine. One of the peptides is identified as a fragment of guinea pig histone H2A having the amino acid sequence corresponding to residues 36-44 of histone H2A, and designated peptide III. WO 03/017920 further discloses human homologues of peptide III including peptide 3 m1, analogs and derivatives thereof, mainly the methylated analogs. WO 03/017920 further discloses other peptides isolated from burned skin, the peptides correspond to fibrinopeptide A and derivatives thereof. The pharmaceutical compositions disclosed in WO 03/017920 are shown to protect against noxious insults and are suggested to be useful for treating inflammatory processes including autoimmune diseases.
None of the peptides disclosed in U.S. Pat. No. 6,468,537 and WO 03/017920 was known to be effective as a scavenger of free radicals or as a metal chelator.
There is still an unmet need for improved medicaments to treat inflammatory and autoimmune diseases, diseases attributable to oxygen free radicals, and diseases characterized by breakdown of the extracellular matrix or connective tissues.